Acetylcholine (ACh) is involved in brain reward and learning functions, and perturbations to this neurotransmitter system may contribute to substance abuse disorders. Animal studies have shown the importance of muscarinic ACh receptors in cocaine reinforced- and non-reinforced-responding, and acetylcholinesterase (AChE) inhibitors reduced methamphetamine-seeking behavior in rodents. Consistent with these findings, a recently completed double-blind placebo-controlled study from our group demonstrated that treatment with the AChE inhibitor rivastigmine reduced craving produced by administration of methamphetamine in the laboratory. In this application, we propose a human laboratory research to evaluate the effects of rivastigmine (3 or 6 mg, daily) or huperzine A (0.4 or 0.8 mg, daily) on craving and reinforcing effects produced by administration of cocaine in cocaine-dependent, non-treatment seeking participants. Rivastigmine is a carbamate derivative that inhibits both AChE and BuChE with equal potency and has selectivity for central activity. Huperzine A is an innovative drug choice for this revised application and is derived from the Chinese herb Huperzia serrata. Huperzine A is a potent cholinesterase inhibitor, and has several other effects in brain (via DA, NMDA and GABA, as well as antioxidant effects and neuroprotection) that may ultimately contribute to its efficacy. In the proposed studies, we will include only participants exhibiting cocaine-induced craving prior to randomization; a strategy predicted to increase statistical power to detect effects of medication treatment on this specific symptom. The public health significance of the proposed project is clear. No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and AChE inhibitors are predicted to be useful for this indication. PUBLIC HEALTH RELEVANCE: No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and acetylcholinesterase inhibitors are predicted to be useful for this indication. To this end, we propose a human laboratory research study to evaluate the effects of rivastigmine or huperzine A on craving and reinforcing effects produced by administration of cocaine.